Jabs, Ethylin W

Objective To evaluate cancer risk in individuals with cleft lip and/or cleft palate (CL/P). Design Retrospective chart review of patients with CL/P, including abstraction of information on cancer diagnoses was conducted. Cancer risk was compared with national population-based estimates using standardized incidence ratios (SIRs) and exact binomial tests. Subgroup analyses compared demographic and clinical characteristics between patients with and without cancer. Setting Study was performed at a single tertiary academic center with multidisciplinary surgical, pediatric, and genetic care. Patients/Participants Total of 2121 patients with CL/P from 1970 to 2024 with complete medical documentation were included. Main Outcome Measures Main outcomes included prevalence of cancer diagnoses, childhood cancer incidence, and differences in cancer occurrence by age, cleft type, syndromic status, and family history. Results Total of 144 patients (6.8%) had pathologically confirmed cancer diagnoses. Twelve childhood cancers were identified, with 10 cases presenting before age 15. Children younger than 15 with CL/P had a significantly elevated cancer risk (SIR 4.7; 95% confidence interval: 1.8-7.6; P < .00001). Pediatric cancers occurred mainly in syndromic cases. Cancer prevalence was higher in cleft palate only and cleft lip/palate cases compared with cleft lip only ( P < .05). Cancer occurrence was not higher in adults with CL/P compared to the general population. Conclusions Cancer risk is not uniformly elevated over the lifespan in individuals with CL/P. Increased cancer risk is observed in our pediatric cohort. Clinical care should include careful assessment of childhood cancers, syndromic features, and family history, with consideration for genetic counseling and multidisciplinary follow-up.

Objective This study aimed to identify specific causes, clinical features, and contributing factors associated with early childhood mortality in a vulnerable subset of patients with cleft lip and/or palate (CL/P) who did not survive to undergo surgical repair. Design This was a retrospective chart review study. Setting The study was conducted at a single tertiary medical center. Patients/Participants We identified 26 liveborn CL/P patients who died without cleft repair from 1970 to 2024. Their data was compared to a control group of 2070 surgically repaired CL/P patients from the same institution. Main Outcome Measures Our primary goal was to characterize the clinical profile of patients experiencing prerepair mortality. Secondary outcomes included identifying causes of death, maternal and prenatal risk factors, and comparing these findings with the surgically repaired patients. Results All 26 unrepaired patients (100%) had genetic syndromes or isolated severe congenital anomalies, a significant difference compared to 24% in the surgically repaired group ( P < .0001). Trisomy 13 (30.8%), holoprosencephaly (23.1%), congenital cardiac defects (11.5%), and trisomy 18 (11.5%) were the leading causes of death. The median age at death for unrepaired patients was 25 days (interquartile range 4-125 days), significantly lower than the 61.9 years in the control group ( P < .0001). Multivariable logistic regression showed that genetic syndromes or severe congenital anomalies were strongly associated with early mortality ( P < .0001). Notably, all unrepaired patients who were born in the United States after 2005 had accurate prenatal diagnoses, which allowed clinical planning before the patients were born. Conclusions Prerepair mortality in CL/P is significantly driven by underlying genetic syndromes or congenital anomalies. For surgeons, this highlights the importance of genetic testing and prenatal care to guide appropriate surgical management. Considering a wait in surgical intervention until patients are approximately 4 months old may allow for better survival assessment and informed decisions for these high-risk individuals.

Objective Congenital facial weakness (CFW) disorders are a heterogeneous group of rare conditions, that present at birth, with reduced facial movement, and mask-like facies. This study utilized a multimodality approach to examine the craniofacial and intraoral phenotypes among CFW disorders: Moebius syndrome (MBS), Hereditary Congenital Facial Palsy (HCFP), β-tubulin isotype 3 syndrome (CFEOM3A-TUBB3), Carey-Fineman-Ziter syndrome (CFZS), and a group of rarer disorders (Other). Design Prospective cohort study. Setting: Dental clinic. Participants: Sixty individuals (sex ratio 1:1, mean age 26.2 ± 17.5 years) with a diagnosis of CFW. Interventions: Deep clinical craniofacial and dental phenotyping, three-dimensional facial surface and cone-beam computed tomography scans, and cephalometric and geometric morphometric analyses. Results CFEOM3A-TUBB3, MBS, and CFZS groups had the highest prevalence of craniofacial anomalies; HCFP individuals were least affected. CFEOM3A-TUBB3 had a higher prevalence of short lower face (75%), poor oral hygiene (100%)/decay (75%), and Class II malocclusion (87.5%). Moebius syndrome was associated with lagophthalmos (90.9%), tongue fissures (72.4%), tight/small oral orifice (51.7%), and tongue fasciculations (50%). Carey-Fineman-Ziter syndrome had oblong facial shape (100%), downward lip commissures (100%), and abnormal hearing (60%). Moderate-severe decay/gingivitis correlated with restricted oral orifice, common among patients with facial animation/sling surgery. Morphologically, the CFW cohort had a relatively small craniofacial centroid size, anthropometric measurements, and distinct craniofacial shapes for each subtype. Conclusions Congenital facial weakness can result in abnormal craniofacial development in addition to the loss of facial movement. Multimodality phenotypic characterization of CFW disorders elucidated key clinical findings and distinct craniofacial shape segregation among the different groups.

Abstract Osteogenic differentiation is essential for bone development, metabolism, and repair; however, the underlying regulatory relationships among genes remain poorly understood. To elucidate the transcriptomic changes and identify novel regulatory genes involved in osteogenic differentiation, we differentiated mesenchymal stem cells (MSCs) derived from 20 human iPSC lines into preosteoblasts (preOBs) and osteoblasts (OBs). We then performed transcriptome profiling of MSCs, preOBs and OBs. The iPSC-derived MSCs and OBs showed similar transcriptome profiles to those of primary human MSCs and OBs, respectively. Differential gene expression analysis revealed global changes in the transcriptomes from MSCs to preOBs, and then to OBs, including the differential expression of 840 genes encoding transcription factors (TFs). TF regulatory network analysis uncovered a network comprising 451 TFs, organized into five interactive modules. Multiscale embedded gene co-expression network analysis (MEGENA) identified gene co-expression modules and key network regulators (KNRs). From these analyses, KLF16 emerged as an important TF in osteogenic differentiation. We demonstrate that overexpression of Klf16 in vitro inhibited osteogenic differentiation and mineralization, while Klf16+/- mice exhibited increased bone mineral density, trabecular number, and cortical bone area. Our study underscores the complexity of osteogenic differentiation and identifies novel regulatory genes such as KLF16, which plays an inhibitory role in osteogenic differentiation both in vitro and in vivo.

Abstract Osteogenic differentiation is essential for bone development, metabolism, and repair; however, the underlying regulatory relationships among genes remain poorly understood. To elucidate the transcriptomic changes and identify novel regulatory genes involved in osteogenic differentiation, we differentiated mesenchymal stem cells (MSCs) derived from 20 human iPSC lines into preosteoblasts (preOBs) and osteoblasts (OBs). We then performed transcriptome profiling of MSCs, preOBs and OBs. The iPSC-derived MSCs and OBs showed similar transcriptome profiles to those of primary human MSCs and OBs, respectively. Differential gene expression analysis revealed global changes in the transcriptomes from MSCs to preOBs, and then to OBs, including the differential expression of 840 genes encoding transcription factors (TFs). TF regulatory network analysis uncovered a network comprising 451 TFs, organized into five interactive modules. Multiscale embedded gene co-expression network analysis (MEGENA) identified gene co-expression modules and key network regulators (KNRs). From these analyses, KLF16 emerged as an important TF in osteogenic differentiation. We demonstrate that overexpression of Klf16 in vitro inhibited osteogenic differentiation and mineralization, while Klf16+/- mice exhibited increased bone mineral density, trabecular number, and cortical bone area. Our study underscores the complexity of osteogenic differentiation and identifies novel regulatory genes such as KLF16, which plays an inhibitory role in osteogenic differentiation both in vitro and in vivo.

ABSTRACTBackgroundPrevious studies of maternal alcohol consumption and craniosynostosis have reported null or inverse associations. We updated a previous analysis of National Birth Defects Prevention Study (NBDPS) data to further examine associations between maternal alcohol consumption and craniosynostosis.MethodsNBDPS was a multi‐site, population‐based case–control study. Mothers of craniosynostosis cases and randomly selected liveborn controls delivered during 1997–2011 completed a telephone interview about pregnancy exposures. We examined associations for self‐reported periconceptional maternal alcohol consumption (during the month before conception through the third gestational month) and odds of craniosynostosis in offspring. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between any alcohol consumption and binge consumption and craniosynostosis, overall and by affected suture. Finally, we performed a probabilistic bias analysis using a range of assumptions about the sensitivity and specificity of self‐reported consumption by case/control status.ResultsWe analyzed interview data from 1435 mothers of craniosynostosis cases and 11,216 mothers of controls. Periconceptional alcohol consumption prevalence was similar among case (36.9%) and control (38.2%) mothers. We observed point estimates near or below 1.0 for alcohol consumption (any and binge) and all suture subtypes of craniosynostosis, with all CIs including the null. Our bias‐adjusted estimates for periconceptional alcohol consumption were higher than our conventional estimates but supported the null findings.ConclusionsWe observed primarily null associations between maternal periconceptional alcohol consumption and craniosynostosis. However, our findings do not diminish the prevailing clinical guidance in the United States that pregnant people should abstain from alcohol consumption.

Congenital facial weakness (CFW) encompasses a heterogenous set of rare disorders presenting with decreased facial movement from birth, secondary to impaired function of the facial musculature. The aim of the present study is to provide an analysis of subject-reported oral health-related quality of life (OHRQoL) in congenital facial weakness (CFW) disorders. Forty-four subjects with CFW and age- and sex- matched controls were enrolled in an Institutional Review Board (IRB)-approved study. Demographic data, medical and surgical history, comprehensive oral examination, and the Oral Health Impact Profile (OHIP-14) were obtained. Compared to unaffected controls, subjects with CFW had higher OHIP-14 scores overall (mean ± SD: 13.11 ± 8.11 vs. 4.46 ± 4.98, p < 0.0001) and within five of seven oral health domains, indicating decreased OHRQoL. Although subjects with Moebius syndrome (MBS) were noted to have higher OHIP-14 scores than those with Hereditary Congenital Facial Paresis (HCFP), there was no significant correlation in OHIP-14 score to age, sex, or specific diagnosis. An increase in OHIP-14 scores in subjects was detected in those who had undergone reanimation surgery. In conclusion, subjects with CFW had poorer OHRQoL compared to controls, and subjects with MBS had poorer OHRQoL than subjects with HCFP. This study provides better understanding of oral health care needs and quality of life in a CFW cohort and suggests that guidelines for dental treatment are required.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.